Enantioselective total synthesis of epothilone A using multifunctional asymmetric catalyses

Article abstract of DOI:10.1002/(SICI)1521-3773(20000103)39:1<209::AID-ANIE209>3.0.CO;2-F

A catalytic version has now been developed for the enantioselective total synthesis of epothilone A (1). The key is the use of multifunctional asymmetric catalySes for a direct aldol reaction and cyanosilylation. This successful approach demonstrated the usefulness of these reactions for the catalytic asymmetric synthesis of complex molecules.

Full text of DOI:10.1002/(SICI)1521-3773(20000103)39:1<209::AID-ANIE209>3.0.CO;2-F

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2: The IR spectrum of 1 in 96% H2SO4 was monitored with time under
groups with a dihedral angle of 608 between the two planes
and in which both CO groups are cisoid (length of the Pt Pt
bond 2.584 Š).[7a] Other related, crystallographically charac-
terized dinuclear platinum carbonyl species include
[{PtCl(CO)(PtBu2Ph)}2][7b] and [{Pt(C6F5)(CO)(PPh3)}2],[7c]
which have dihedral angles of 70.18 and 78.68, and Pt Pt
distances of 2.628 and 2.599(Š), respectively. Preliminary
reports have also appeared for [{PtCl(CO)(PPh3)}2][8] and, in
all cases, the carbonyl groups are cis and the two phosphanes
are trans to the Pt Pt bond.
1
evacuation (0.001 Torr). When the band for 1 (2174 cm for 12CO and
1
2126 cm for 13CO) had disappeared (ca. 1 d), nitrogen was admitted to
the solution, which contained only 2 and a black colloidal precipitate of Pt
metal. The solution of 2 was transferred under nitrogen by canula and used
for all the spectroscopic measurements. This solution is indefinitely stable
under a nitrogen atmosphere.
Received: July 29, 1999 [Z13795]
[1] H. Willner, F. Aubke, Angew. Chem. 1997, 109, 2506 ± 2530; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2403 ± 2425.
[2] a) C. Wang, M. Bodenbinder, H. Willner, S. Rettig, J. Trotter, F.
Aubke, Inorg. Chem. 1994, 33, 779 ± 786; b) M. Bodenbinder, G.
Balzer-Jöllenbeck, H. Willner, R. J. Batchelor, F. W. B. Einstein, C.
Wang, F. Aubke, Inorg. Chem. 1996, 35, 82 ± 92.
[3] K. Nakamoto, Infrared Spectra of Inorganic Compounds and Coor-
dination Compounds, Wiley, New York, 1st ed., 1963, p. 72.
[4] a) G. Longoni, P. Chini, J. Am. Chem. Soc. 1976, 98, 7225 ± 7231;
b) D. M. Washecheck, E. J. Wucherer, L. F. Dahl, A. Ceriotti, G.
Longoni, M. Manassero, M. Sansoni, P. Chini, J. Am. Chem. Soc. 1979,
101, 6110 ± 6112.
[5] a) G. Hwang, M. Bodenbinder, H. Willner, F. Aubke, Inorg. Chem.
1993, 32, 4667 ± 4669; b) G. Hwang, C. Wang, M. Bodenbinder, H.
Willner, F. Aubke, J. Fluorine Chem. 1994, 66, 159 ± 166; c) G. Hwang,
C. Wang, F. Aubke, H. Willner, M. Bodenbinder, Can. J. Chem. 1993,
71, 1532 ± 1536.
It has been shown that there is no correlation of d(Pt Pt)
with 1J(Pt,Pt') in closely related dinuclear platinum com-
1
plexes.[8] It is worth noting that J(Pt,Pt') for 1 is 550.9 Hz,
while the values for [{PtCl2(CO)}2]2 (5250 Hz)[9] and
[{PtCl(CO)(PPh3)}2] (760 Hz)[8] are widely different, although
other related coupling constants are similar (see Table 1 and
refs. [8, 9]).
Prolonged evacuation of 1 results in disproportionation and
formation of 2 through loss of CO [see Eq. (2)]. In this case,
13C and 195Pt NMR measurements on unenriched and 99%
13CO-enriched 2 show that there are two magnetically
equivalent carbonyl groups per platinum with no 195Pt 195Pt
coupling; 2 is thus a monomer. We presently favor a square-
planar platinum(ii) center with two CO ligands in a cis
configuration, consistent with both IR and Raman measure-
ments; the CO stretching frequencies are close to those for
cis-[Pt(CO)2(SO3F)2],[5b] but higher than those for cis-
[Pt(CO)2Cl2].[10] It is difficult to be sure whether the other
two coordination sites on platinum are occupied by a
[6] K. Mogi, Y. Ichihashi, Q. Xu, unpublished results.
[7] a) A. Modinos, P. Woodward, J. Chem. Soc. Dalton Trans. 1975, 1516 ±
1520; b) C. Couture, D. H. Farrar, D. S. Fisher, R. R. Gukathasan,
Â
Â
Organometallics 1987, 6, 532 ± 536; c) R. Uson, J. Fornies, P. Espinet,
Â
Ä
C. Fortuno, M. Tomas, A. J. Welch, J. Chem. Soc. Dalton Trans. 1989,
1583 ± 1587.
[8] N. M. Boag, J. Browning, C. Crocker, P. L. Goggin, R. J. Goodfellow,
M. Murray, J. L. Spencer, J. Chem. Res. (M) 1978, 2962 ± 2983.
[9] N. M. Boag, P. L. Goggin, R. J. Goodfellow, I. R. Herbert, J. Chem.
Soc. Dalton Trans. 1983, 1101 ± 1107.
[10] J. Browning, P. L. Goggin, R. J. Goodfellow, M. G. Norton, A. J. M.
Rattray, B. F. Taylor, J. Mink, J. Chem. Soc. Dalton Trans. 1977, 2061 ±
2067.
2
2
bidentate SO4 or by two monodentate SO4 /HSO4 groups
since it is impossible to obtain any useful IR or Raman data in
the sulfato region. However, when 1 is in concentrated H2SO4,
it seems more probable that the other two sites are occupied
by monodentate HSO4 groups as recently found for sil-
ver(i).[11]
[11] D. B. DellꢁAmico, F. Calderazzo, F. Marchetti, Chem. Mater. 1998, 10,
524 ± 530.
The discovery of 1 suggests that homoleptic cationic
carbonyl complexes of late transition metals in low oxidation
states can be formed in media which are less acidic than the
superacids that have been used previously. We found that this
unusual dinuclear platinum carbonyl complex, 1, exhibits high
catalytic activity for the carbonylation of olefins;[12] future
studies will investigate the detailed reaction mechanism of
this catalytic activity and attempts will be made to obtain 1 as
a crystalline salt.
[12] Q. Xu, Y. Souma, Top. Catal. 1998, 6, 17 ± 26.
Enantioselective Total Synthesis of
Epothilone A Using Multifunctional
Asymmetric Catalyses**
Daisuke Sawada and Masakatsu Shibasaki*
Experimental Section
Epothilones (see Scheme 1 for epothilones A (1) and B (2))
show potent antitumor activity by binding and stabilizing
microtubules in the same way as taxol, and they are promising
drug candidates. Epothilones A and B were isolated from the
Standard canula transfer techniques were used for all sample manipula-
tions. NMR spectra were recorded in D2SO4 at room temperature on a
Bruker AMX 200. The 13C chemical shifts were referenced to external
tetramethylsilane (TMS), and 195Pt chemical shifts were referenced to
42.8 MHz at such a magnetic field that the protons in external TMS
resonate at exactly 200 MHz. NMR simulations were carried out using
gNMR 4.1 (Cherwell Scientific, Oxford, UK). Infrared spectra were
obtained on thin films between two silicon discs on a JASCO FT/IR-230
spectrometer. Raman spectra were recorded on a Nicolet FT-Raman 960
spectrometer.
[*] Prof. Dr. M. Shibasaki D. Sawada
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (‡ 81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
1: PtO2 (2 mmol) in 96% H2SO4 (10 mL) was vigorously stirred for 2 weeks
under 12CO at constant pressure (1 atm), whereupon the dark colloidal
suspension became colorless. The resulting solution is very moisture
sensitive. Complex 1 with 99% 13CO was prepared similarly.
[**] This study was financially supported by CREST. We thank Dr.
Motomu Kanai, Yoshitaka Hamashima, and Rie Namme for their
support and fruitful discussion.
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209

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catalytic
asymmetric
cyanosilylation
S
N
S
N
S
S
N
I
N
CN
OH
H
O
O
CHO
OAc
H
OH
3
O
R
O
OH
Ph
OPh
1: epothilone A (R = H)
2: epothilone B (R = Me)
O
O
OH
O
TBSO
O
O
OTBS
4
direct catalytic
asymmetric
aldol reaction
catalytic
asymmetric
epoxidation
O
H
OBn
OBn
O
O
O
O
O
Scheme 1. Retrosynthetic analysis of 1.
myxobacteria of the genus Sorangium, and their structures
were determined by Höfle et al.[1] Highly efficient total
syntheses of epothilones were disclosed by the research
groups of Danishefsky, Nicolaou, and Schinzer,[2] but an
enantioselective total synthesis using simple asymmetric
catalysts has not been acheived.[3] Herein we report an
enantioselective total synthesis of epothilone A (1) using
multifunctional asymmetric catalyses for direct aldol reaction
and cyanosilylation, demonstrating the usefulness of these
reactions for the catalytic asymmetric synthesis of complex
molecules.
S
N
S
N
S
N
c
a, b
R
CO2Et
CHO
6
OH
5
7: R = CN
8: R = CO2Et
d
S
S
N
g, h
e, f
N
CHO
OTBS
OTBS
TMS
9
10
Scheme 1 shows our retrosynthetic strategy. Epothilone A
(1) was disconnected into two fragments, 3 and 4. The 16-
membered ring of 1 was expected to be constructed by Suzuki
coupling of 3 and 4 followed by lactonization. The vinyl iodide
3 could be obtained by a catalytic asymmetric cyanosilylation
controlled by a Lewis acid ± Lewis base bifunctional catalyst.[4]
The ester 4 could be synthesized by a catalytic asymmetric
epoxidation and aldol reaction.[5, 6]
The known ester 5 was converted into aldehyde 6 in two
steps for the synthesis of fragment 3 (Scheme 2).[2b] We then
examined a catalytic asymmetric cyanosilylation of 6 using a
Lewis acid ± Lewis base bifunctional catalyst containing
ligand 12 (>1-g scale).[4] With use of 10 mol% of the catalyst,
cyanohydrin 7 was obtained in excellent yield and enantio-
meric excess (97% yield, 99% ee) after acid workup.[7]
Conversion of the cyanohydrin into the ester 8 by acidic
ethanolysis followed by protection and reduction resulted in
the aldehyde 9. Addition of lithium acetylide to 9 afforded the
alcohol product as a mixture of diastereomers, which was
directly treated with methyl chloroformate to give the methyl
carbonate. Reductive deoxygenation with palladium provided
the trimethylsilylalkyne 10.[8] Removal of the silyl group,
hydrotitanation, and aqueous workup gave (Z)-silylalkene 11,
which was easily converted into the vinyl iodide 3.[9]
S
N
S
N
i, j
k, l
I
TMS
OAc
OH
3
11
P(O)Ph2
OH
(S) -
OH
P(O)Ph2
12
ˆ
Scheme 2. a) DIBAL-H, CH2Cl2,
788C, 70%; b) Ph3P C(Me)CHO,
benzene, reflux, 90%; c) Et2AlCl, ligand 12, TMSCN, Bu3P(O), CH2Cl2,
408C, 97%, 99% ee; d) H2SO4, EtOH, reflux, 75%; e) tBuMe2SiCl,
ꢀ
imidazole, DMF, 99%; f) DIBAL-H, toluene, 788C, 87%; g) Me3SiC -
CLi, THF, 788C; then methyl chloroformate, 79%; h) Pd(OAc)2, Bu3P,
HCO2NH4, benzene, 508C, 51%; i) AcOH, THF, H2O, 508C, 89%;
j) [Ti(OiPr)4], iPrMgCl, Et2O, 78 ! 508C, 90%; k) I2, CH2Cl2, 65%;
l) Ac2O, Et3N, DMAP, CH2Cl2, 90%. Bn ˆ benzyl, DIBAL-H ˆ diisobu-
tylaluminum hydride, TBS ˆ tert-butyldimethylsilyl, TMS ˆ trimethylsilyl.
monobenzyl ether 14, which was then oxidized to aldehyde 15
(Scheme 3). The lithium enolate of butanone was allowed to
react with 15, and the resulting alcohol was transformed into
enone 16 by the use of trifluoroacetic anhydride and DBU. As
planned a catalytic asymmetric epoxidation of 16 was
extensively examined.[5] However, because of the steric
hindrance of the quaternary carbon atom in the a-position
to the double bond, only small amounts of the epoxide were
The synthesis of fragment 4 started with commercially
available neopentyl glycol 13. Compound 13 was protected as
210
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diol as the major compound (ca. 7:1), which was then
protected as an acetonide (!22).[12] The benzyl group of 22
was cleaved under Birch reduction conditions, and the
resulting alcohol was oxidized to aldehyde 23, which was a
key compound for the crucial catalytic resolution. We
examined a direct catalytic asymmetric aldol reaction of
acetophenone with (Æ)-23 using the heteropolymetallic
catalyst [LaLi3{tris(binaphthoxide)}] (LLB) with KOH and
H2O.[6] Gratifyingly, as expected, the resolution was achieved
and the two diastereomers 24 and 25 were formed with high ee
values in a catalyst-controlled manner using 20 mol% of
catalyst (30% yield, 89% ee for 24; 29% yield, 88% ee for 25;
recovery of 23, 30%).[13]
Thus we succeeded in obtaining the two optically active
compounds 24 and 25 simultaneously, and therefore a strategy
of this type would be useful for exploring the diversity of
epothilones in terms of medicinal chemistry. As far as we
know, this is the first example of a catalytic resolution of the
racemic compound in an aldol reaction using a simple
asymmetric catalyst.[2k] The desired compound 24 for the
synthesis of epothilone A was transformed into phenyl ester
26 using bis(trimethylsilyl) peroxide (BTSP) and SnCl4; the
terminal olefin remained unchanged.[14] Deprotection and
selective reprotection of hydroxyl moieties gave 27, which was
immediately oxidized to 4 by Dess ± Martin periodinane to
avoid the undesired cyclization of hydroxy and ester moieties.
Suzuki coupling of fragments 3 and 4 and subsequent
hydrolysis under basic conditions afforded the hydroxy acid
29 (Scheme 5).[2a] Ring closure of 29 under Yamaguchi
conditions afforded cyclic compound 30.[2d,g,i±k] Finally remov-
al of the two TBS groups and epoxidation of the ring olefin
functionality afforded 1.[2a,c,i,j]
c,d
b
OBn
H
OBn
HO
a
OR
O
O
16
13 : R = H
14 : R = Bn
15
O
g
e
OBn
OBn
X
OH
X
17 : X = O
18 : X = N~OMe
19 : X = N~OMe
20 : X = O
f
h
Scheme 3. a) NaH, BnBr, DMF, 72%; b) SO3 ´ Py, DMSO, Et3N, 96%;
c) LDA, butanone, THF, 788C, 81%; d) trifluoroacetic anhydride,
CH2Cl2, then DBU, 100%; e) H2O2, NaOH (aq), MeOH, 66%; f) NH2-
OMe ´ HCl, AcONa, MeOH, 83%; g) CuCN, MeLi, Et2O, 788C, 60%;
h) Raney nickel (W2), H2, H3BO3, acetone, THF, MeOH, H2O, 78%.
DBU ˆ 1,8-diazabicyclo[5.4.0]undec-7-ene, LDA ˆ lithium diisopropyl-
amide, Py ˆ pyridine.
obtained with low ee values. This unfortunate result led us to
another strategy for the synthesis of optically active 4. We
envisioned that a direct aldol reaction of acetophenone with
(Æ)-23 (see Scheme 4) promoted by a heteropolymetallic
asymmetric catalyst would give the desired 24 by an effective
catalyst-controlled process. Toward this end, 16 was oxidized
with H2O2 to the epoxy ketone 17, which was then converted
into methyloxime 18 (Scheme 3). The epoxide opening to give
anti-aldol 20 was achieved using cuprate reagent (!19) and
subsequent reduction with Raney nickel followed by hydrol-
ysis.[10] To the best of our knowledge, this is a new method to
prepare an anti-aldol.[11]
The lithium enolate of aldol 20 was treated with allyl
bromide to give 21 as a single stereoisomer (Scheme 4).[12]
Reduction of 21 with Me4NBH(OAc)3 provided the desired
H
OBn
b, c
d, e
OBn
OBn
a
O
O
f
O
O
O
O
O
OH
OH
(±) - 22
(±) - 20
(±) - 21
(±) - 23
g
h, i
Ph
Ph
OPh
OPh
O
O
O
O
O
O
OH
OH
O
O
OH
O
TBSO
O
OH OTBS
24
25
26
27
j
NHTs
NHTs
(±) –
OPh
TBSO
O
OTBS
O
28
4
Scheme 4. a) LHMDS, allyl bromide, DMPU, THF, 788C, 48% (recovery of 20 52%); b) Me4NBH(OAc)3, AcOH, MeCN, 74%; c) methoxypropene,
TsOH, DMF, 96%; d) Li, liq. NH3, tBuOH, THF, 100%; e) TPAP, NMO, 4-Š molecular sieves, CH2Cl2, 89%; f) acetophenone, (R)-LLB, KHMDS, H2O,
THF, 208C, 30% (89% ee) for 24, 29% (88% ee) for 25 (recovery of 23 36%); g) BTSP, SnCl4, 4-Š molecular sieves, ligand 28, K2CO3, CH2Cl2, 71%;
h) BCl3, CH2Cl2, 788C, 77%; i) TBSOTf, iPr2NEt, CH2Cl2, 100%; j) Dess ± Martin periodinane, CH2Cl2, 65%. BTSP ˆ bis(trimethylsilyl) peroxide,
DMPU ˆ 1,3-dimethylhexahydro-2-pyrimidinone, KHMDS ˆ potassium bis(trimethylsilyl)amide, LHMDS ˆ lithium bis(trimethylsilyl)amide, LLB ˆ [La-
Li3{tris(binaphthoxide)}], NMO ˆ 4-methylmorpholine N-oxide, OTf ˆ trifluoromethanesulfonate, TPAP ˆ tetrapropylammonium perruthenate, Ts ˆ tol-
uene-4-sulfonyl.
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stirred for further 30 min. The organic layer was separated and washed with
water. The aqueous layer was extracted with ethyl acetate (2 Â 30 mL). The
combined organic layers were washed with brine and dried over Na2SO4.
The crude product was further purified by flash chromatography (ethyl
acetate/hexane 1/3) to give 7 (1.18 g, 97%, 99% ee).
S
S
N
N
I
H
OH
CO2H
OTBS
OAc
a, b
3
General procedure for the epoxide opening reaction using a cuprate
reagent (see Table 1, entry 1):[11] To a suspension of CuCN in diethyl ether
was added methyllithium in diethyl ether (4.9 mL, 5.36 mmol, 1.1m) at
788C. Then the temperature was gradually raised to 08C, and the mixture
was stirred for 20 min to give a clear solution. To the solution was added the
epoxy-oxime (99.3 mg, 0.54 mmol) in diethyl ether (2.0 mL), and the
resulting mixture was stirred for 24 h at the same temperature. Then
saturated aqueous NH4Cl and aqueous NH3 were added, and the mixture
was stirred at room temperature for 1 h. The organic layer was separated
and aqueous layer was extracted with ethyl acetate (2 Â 30 mL). The
combined organic layers were washed with brine and dried over Na2SO4.
The crude product was further purified by flash chromatography (ethyl
acetate/hexane 1/20) to give the methyloxime alcohol (83 mg, 77%).
OPh
O
OTBS
TBSO
O
O
OTBS
4
29
c
S
N
S
N
H
H
O
O
O
O
H
OH
OTBS
O
d, e
Received: September 1, 1999 [Z13949]
H
O
O
OH
OTBS
[1] G. Höfle, N. Bedolf, H. Steinmetz, D. Schomburg, K. Gerth, H.
Reichenbach, Angew. Chem. 1996, 108, 1671 ± 1673; Angew. Chem.
Int. Ed. Engl. 1996, 35, 1567 ± 1569.
30
1
Scheme 5. a) 9-BBN (2 mol equiv), THF, then [PdCl2(dppf)] (50 mol%),
K3PO4, DMF, H2O, 608C, 50%; b) NaOH (aq), MeOH, 84%; c) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, then DMAP, toluene, 88%; d) HF ´
[2] a) A. Balog, D. Meng, T. Kamenecka, P. Bertinato, D.-S. Su, E. J.
Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976 ± 2978;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2801 ± 2803; b) Z. Yang, Y. He,
D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem. 1997, 109,
170 ± 172; Angew. Chem. Int. Ed. Engl. 1997, 36, 166 ± 168; c) D.
Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, Angew.
Chem. 1997, 109, 543 ± 544; Angew. Chem. Int. Ed. Engl. 1997, 36, 523 ±
524; d) K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, Angew.
Chem. 1997, 109, 539 ± 540; Angew. Chem. Int. Ed. Engl. 1997, 36, 525 ±
527; e) D.-S. Su, D. Meng, P. Bertinato, A. Balog, E. J. Sorensen, S. J.
Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B. Horwitz, Angew.
Chem. 1997, 109, 775 ± 777; Angew. Chem. Int. Ed. Engl. 1997, 36, 757 ±
759; f) K. C. Nicolaou, N. Winssinger, J. Pastor, S. Ninkovic, F.
Sarabia, Y. He, D. Vourloumis, Z. Yang, T. Li, P. Giannakakou, E.
Hamel, Nature 1997, 387, 268 ± 272; g) K. C. Nicolaou, Y. He, D.
Vourloumis, H. Vallberg, F. Roschangar, F. Sarabia, S. Ninkovic, Z.
Yang, J. I. Trujillo, J. Am. Chem. Soc. 1997, 119, 7960 ± 7973; h) K. C.
Nicolaou, S. Ninkovic, F. Sarabia, D. Vourloumis, Y. He, H. Vallberg,
M. R. V. Finlay, Z. Yang, J. Am. Chem. Soc. 1997, 119, 7974 ± 7991;
i) D. Meng, P. Bertinato, A. Balog, D.-S. Su, T. Kamenecka, E. J.
Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073 ±
10092; j) C. R. Harris, S. D. Kuduk, A. Balog, K. Savin, P. W. Glunz,
S. J. Danishefsky, J. Am. Chem. Soc. 1999, 121, 7050 ± 7062; k) S. C.
Sinha, C. F. Barbas III, R. A. Lerner, Proc. Natl. Acad. Sci. USA 1998,
14603 ± 14608; l) review: K. C. Nicolaou, F. Roschangar, D. Vourlou-
mis, Angew. Chem. 1998, 110, 2120 ± 2153; Angew. Chem. Int. Ed.
1998, 37, 2014 ± 2045; m) J. Mulzer, A. Mantoulaidis, E. Ohler,
Tetrahedron Lett. 1998, 39, 8633 ± 8636; n) S. A. May, P. A. Grieco, J.
Chem. Soc. Chem. Commun. 1998, 1597 ± 1598; o) D. Schinzer, A.
Bauer, J. Schieber, Synlett 1998, 861 ± 864; p) J. D. White, R. G. Carter,
K. F. Sundermann, J. Org. Chem. 1999, 64, 684 ± 685; q) D. Schinzer,
A. Bauer, O. M. Böhm, A. Limberg, M. Cordes, Chem. Eur. J. 1999, 5,
2483 ± 2491; r) D. Schinzer, A. Bauer, J. Schieber, Chem. Eur. J. 1999,
5, 2492 ± 2500.
pyridine, THF, 99%; e) 3,3-dimethyldioxirane, CH2Cl2,
358C, 49%.
9-BBN ˆ 9-borabicyclo[3.3.1]nonane, DMAP ˆ 4-dimethylaminopyridine,
dppf ˆ 1,1'-bis(diphenylphosphanyl)ferrocene.
In summary we have succeeded in an enantioselective total
synthesis of epothilone A (1) using multifunctional asymmet-
ric catalyses with a direct aldol reaction and cyanosilylation as
key steps.
Experimental Section
24, 25: To a stirred solution of KHMDS in toluene (532 mL, 0.266 mmol,
0.5m) at 08C was added a solution of water in THF (590 mL, 0.59 mmol,
1.0m). The resulting solution was stirred for 20 min at 08C, and then (R)-
LLB in THF (2.95 mL, 0.295 mmol, 0.1m) was added and the mixture was
stirred at 08C for 30 min. The pale yellow solution thus obtained was then
cooled to 208C, and acetophenone (1.38 mL, 11.8 mmol) was added. The
solution was stirred for 20 min at this temperature and then 23 (397 mg,
1.48 mmol) was added and the reaction mixture was stirred for 168 h at
208C. The reaction was quenched by addition of 1n HCl (4 mL), and the
aqueous layer was extracted with ethyl acetate (3 Â 30 mL). The combined
organic layers were washed with brine and dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified by flash
chromatography (SiO2, ethyl acetate/hexane 1/30) to give 24 (172 mg,
30%, 89% ee) and 25 (166 mg, 29%, 88% ee).
7: Ligand 12 (447 mg, 0.625 mmol) was placed in a flame-dried flask and
dried at 508C for 2 h under reduced pressure. Dichloromethane (2 mL) was
added, followed by the addition of diethylaluminum chloride in hexane
(651 mL, 0.625 mmol, 0.96m) under argon atmosphere. After the mixture
was stirred for 10 min, tributylphosphane oxide (546 mg, 2.5 mmol) in
dichloromethane (1.8 mL) was added at room temperature. The resulting
mixture was stirred at the same temperature for 1 h to give a clear solution.
To this stirred solution of the catalyst was added 6 (1.045 g, 6.25 mmol) in
dichloromethane (13.8 mL) at 408C. After 30 min TMSCN (1.0 mL,
7.5 mmol) was slowly added over 24 h with a syringe pump. (Because the
melting point of TMSCN is 11 ± 128C, it should be added dropwise from the
top of the flask, where the temperature may be above 158C.) The reaction
mixture was stirred for 39 h at the same temperature. Trifluoroacetic acid
(2.0 mL) was added at 408C, and the mixture was stirred vigorously at
room temperature for 1 h to hydrolyze the trimethylsilyl ether moiety of
the product. After the addition of ethyl acetate (30 mL), the mixture was
[3] For an enantioselective total synthesis of epothilone A using antibody
catalysis, see reference [2k].
[4] Y. Hamashima, D. Sawada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
1999, 121, 2641 ± 2642.
[5] a) M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J. Am.
Chem. Soc. 1997, 119, 2329 ± 2330; b) S. Watanabe, Y. Kobayashi, T.
Arai, H. Sasai, M. Bougauchi, M. Shibasaki, Tetrahedron Lett. 1998,
39, 7353 ± 7356; c) S. Watanabe, T. Arai, H. Sasai, M. Bougauchi, M.
Shibasaki, J. Org. Chem. 1998, 63, 8090; d) K. Daikai, M. Kamaura, J.
Inanaga, Tetrahedron Lett. 1998, 39, 7321 ± 7322.
[6] a) Y. M. A. Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Angew.
Chem. 1997, 109, 1942 ± 1944; Angew. Chem. Int. Ed. Engl. 1997, 36,
212
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Angew. Chem. Int. Ed. 2000, 39, No. 1

COMMUNICATIONS
1871 ± 1873; b) N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M.
Shibasaki, J. Am. Chem. Soc. 1999, 121, 4168 ± 4178.
[7] The absolute configuration was determined by Mosherꢁs method; see
J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512 ± 519. The
enantiomeric excess was determined by HPLC analysis using DAI-
CEL CHIRALPAK AD (2-propanol/hexane 1/100).
[8] a) T. Mandai, T. Matsumoto, M. Kawada, J. Tsuji, Tetrahedron Lett.
1993, 34, 2161 ± 2164; b) J. Tsuji, T. Sugiura, I. Minami, Synthesis 1987,
603 ± 606.
Enantioselective Construction of Vicinal
Stereogenic Quaternary Centers by
Dialkylation: Practical Total Syntheses
of (‡)- and meso-Chimonanthine**
Larry E. Overman,* Jay F. Larrow, Brian A. Stearns,
and Jennifer M. Vance
[9] a) K. Harada, H. Urabe, F. Sato, Tetrahedron Lett. 1995, 36, 3203 ±
3206; b) F. Sato, H. Ishikawa, M. Sato, Tetrahedron Lett. 1981, 22, 85 ±
88. This method could lead to the fragment for the synthesis of
epothilone B (2).
[10] For related work with oximes, see E. J. Corey, L. S. Melvin, Jr., M. F.
Haslanger, Tetrahedron Lett. 1975, 3117 ± 3120.
[11] We can also prepare syn-aldol from cis-enone by this method.[13]
Through coupling with the stereocontrolled catalytic asymmetric
epoxidation of the cis- and trans-enones recently developed in our
group,[5] it is possible to prepare syn- and anti-aldol from cis- and trans-
enones, respectively, with excellent ee values (Table 1).
Enantioselective formation of vicinal stereogenic quater-
nary carbon centers is one of the more formidable challenges
in contemporary organic synthesis.[1, 2] Here we report a
powerful method for creating such arrays by reaction of
achiral dienolates with a chiral, enantiopure dielectrophile.
The method was developed to address the vicinal stereogenic
quaternary benzylic carbon centers that are the signature
structural feature of indole alkaloids containing the hexacyclic
3a,3a'-bispyrrolidino[2,3-b]indoline unit.
The chimonanthines are the simplest members of this
family and are found in nature in all three stereochemical
motifs: meso-chimonanthine (1)[3] and ( )-chimonanthine[4]
from plant sources; (‡)-chimonanthine (2) from the skin of a
Colombian frog[5] and from plant sources.[6] In addition, many
Table 1. Epoxide opening of cis-epoxy-oximes by cuprate reagents.
R3
O
R1
R2
OH
R1
R3Li, CuCN
Et2O
R2
N
N
MeO
MeO
Entry
R1
R2
R3
Yield [%]
1
2
3
4
5
6
7
methyl
propyl
pentyl
pentyl
pentyl
pentyl
pentyl
pentyl
phenethyl
methyl
methyl
methyl
butyl
phenyl
vinyl
77
72
85
80
80
50
81
phenethyl
phenethyl
phenethyl
phenethyl
pentyl
methyl
[12] The relative configuration of the alcohol resulting from reduction of
21 with Me4NBH(OAc)3 was determined by analyzing the NOE of 22,
and the relative configuration of the methyl group of 22 resulting from
allylation of 20 was further deter-
mined by transforming 22 into 31 and
analyzing the coupling constant be-
Ha
OBn
tween Ha and Hb (10.2 Hz).
Hb
[13] The absolute configurations were de-
termined by Mosherꢁs method,[8] and
the enantiomeric excesses were deter-
mined by HPLC analysis using DAI-
CEL CHIRALPAK AD (2-propanol/
O
OH
O
31
hexane 1/100). The relative configurations were determined by
transforming 24 into 32 and 25 into 33 (cyclization of 27 and 34,
respectively), and analyzing their NOEs.
[*] Prof. L. E. Overman, Dr. J. F. Larrow, B. A. Stearns, J. M. Vance
Department of Chemistry
OTBS
OTBS
University of California, Irvine
TBSO
OH
O
O
516 Rowland Hall, Irvine, CA 92697-2025 (USA)
Fax: (‡1)949-824-3866
O
O
E-mail: leoverma@uci.edu
33
32
[**] This research was supported by the NIH (grant GM-12389), Bristol-
Myers Squibb Pharmaceuticals (graduate fellowship to B.A.S.), the
American Cancer Society (postdoctoral fellowship to J.F.L., PF-98-
003), and Pfizer (undergraduate research fellowship to J.M.V). NMR
and mass spectra were determined at University of California, Irvine
with instruments purchased with the assistance of the NSF and NIH
shared instrumentation programs. We are grateful to Dr. Joseph Ziller
and Dr. John Greaves for their assistance with X-ray and mass
spectrometric analyses.
OPh
OH
OH OTBS O
34
[14] R. Göttlich, K. Yamakoshi, H. Sasai, M. Shibasaki, Synlett 1997, 971 ±
973.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
Angew. Chem. Int. Ed. 2000, 39, No. 1
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213